Leptin is a neurohormone that acts in the hypothalamus to regulate energy balance and food intake (Wauters et al., 2000, Eur. J. Endocrinol, 143:293-311). Recessive mutations in leptin or the gene for its receptor, ObR, result in profound obesity and type II diabetes mellitus (Zhang et al., 1994, Nature 372:425-432). In addition to its role as a neurohormone, leptin can modulate immune response, fertility, and hematopoiesis, acting as a mitogen, metabolic regulator, or pro-angiogenic factor (Wauters et al., 2000, Eur. J. Endocrinol. 143:293-311).
The amino acid sequence of leptin (SEQ ID NO:1) was described by Masuzaki et al. (Diabetes 1995, 44:855-858). Leptin binds to multiple isoforms of its receptor ObR. For example, the signaling pathways activated by leptin receptor isoform ObR1 upon leptin binding include the classic cytokine JAK2/STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) pathway, the Ras/ERK1/2 (Ras/extracellular signal-regulated kinases 1/2) signaling cascade, and the PI3K/Akt/GSK3 (phosphoinositide 3 kinase/protein kinase B/glycogen synthase kinase 3) growth/anti-apoptotic pathway. In addition, leptin has been found to induce PLC-γ (phospholipase C-gamma), PKC (protein kinase C), p38 kinase, and nitric oxide (NO) production (Bjorbaek et al., 1997, J. Biol. Chem. 272:32686-32695; Sweeney, 2002, Cell. Signal. 14:655-663; Zabeau et al., 2003, FEBS Lett. 546:45-50). Ultimately, induction of ObR1 may activate several genes involved in cell proliferation, including c-fos, c-jun, junB, egr-1, and socs3, and upregulate the expression angiogenic factors, such as VEGF (Sweeney, 2002, Cell. Signal. 14:655-663; Zabeau et al., 2003, FEBS Lett. 546:45-50; Frankenberry et al., 2004, Am. J. Surg. 188:560-565).
The residues around residue 40 of leptin are labeled as site I, those residues at the very N-terminus and in the middle of the protein are labeled as binding site II, and the residues at the C-terminus are labeled as binding site III. Interfering with these binding surfaces may increase or decrease the efficiency of downstream ObR signaling. Full-length leptin and point mutants of full-length leptin have been examined as potential therapeutic agents for obesity, but the results were disappointing, largely due to leptin resistance in obese people as well as difficulties in recombinant leptin delivery to the central nervous system (Montez et al., 2005, Proc. Natl. Acad. Sci. USA 102:2537-2542).
As a first indication of the possibility of growth arrest upon ObR inactivation, the proliferation rate of leptin-sensitive BAF/3 cells stably transfected with the long form of human leptin receptor was measured after treatment of leptin fragments and their mutants (Niv-Spector et al., 2005, Biochem. J. 391:221-230). It was found that single-point mutations in leptin binding site III lower the affinity between the ligand and the receptor, drastically attenuating the agonistic activity and converting those mutants into both partial antagonists and weak agonists.
The multiple roles that leptin plays in various biological processes suggest that it is not straightforward to obtain true agonists or antagonists that do not change the downstream signaling effect upon varying environmental conditions. Indeed, the emergence of both partial antagonists and weak agonists as listed above indicates that, depending upon the cell lines used, as well as the presence or absence of native, unmodified leptin, the same mutant protein or large subunit can trigger different biological responses. The use of such proteins and peptides in human or veterinary therapy may be problematic, as the peptides do not demonstrate pure, controllable agonist or antagonistic activity against the leptin receptor.
In the context of energy balance, leptin plays a key role in regulating energy balance and food intake. Disruption in normal leptin production or activity causes severe obesity cases in affected individuals. It is thus possible that a leptin antagonist could be used to purposefully cause weight gain or stop weight loss in individuals with a severe case of nutrition disorder, such as cachexia or wasting. Cachexia is the term used to define weight loss, muscle atrophy, fatigue, weakness and significant appetite loss in an individual who is not actively trying to lose weight. Cachexia is generally associated with cancer, metabolic acidosis (from decreased protein synthesis and increased protein catabolism), infectious diseases (such as tuberculosis and AIDS), autoimmune disorders or drug addiction. This condition physically weakens patients to a state of immobility stemming from loss of appetite, asthenia and anemia, and response to standard treatment is usually poor. Wasting refers to the process by which a debilitating disease causes muscle and fat tissue to “waste” away. Wasting is sometimes referred to as “acute malnutrition” because it is believed that episodes of wasting have a short duration, in contrast to stunting, which is regarded as chronic malnutrition. Wasting can be caused by an extremely low energy intake (e.g., caused by famine), nutrient losses due to infection, or a combination of low intake and high loss. Infections associated with wasting include tuberculosis, chronic diarrhea, and AIDS. The mechanism may involve cachectin (also called tumor necrosis factor), a macrophage-secreted cytokine. Voluntary weight loss and eating disorders are excluded as causes of wasting. A leptin antagonist that is able to act on the leptin receptors located in the central nervous system should be able to counterbalance or mitigate the negative effects of cachexia or wasting on an individual.
In the context of cancer, it is noteworthy that leptin expression can be induced under hypoxic conditions, which often occur in solid tumors (Ambrosini et al., 2002, J. Biol. Chem. 277(37):34601-34609; Grosfeld et al., 2002, J. Biol. Chem. 277(45):42953-42957). Hypoxia and chemical inducers of cellular hypoxia are able to activate the leptin gene promoter through the hypoxia-induced factor-1 (HIF-1) in human adipocytes and fibroblasts (Ambrosini et al., 2002, J. Biol. Chem. 277(37):34601-34609; Grosfeld et al., 2002, J. Biol. Chem. 277(45):42953-42957). These data suggest that leptin may play a role in vascular remodeling (Stenmark et al., 2002, Chest 122 (6 Suppl):3265-3345). Indeed, leptin has been shown to regulate neo-angiogenesis by itself and in concert with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) (Bouloumie et al., 1998, Circ. Res. 83(10):1059-1066; Sierra-Honigmann et al., 1998, Science 281(5383):1683-1686; Cao et al., 2001, Proc. Natl. Acad. Sci. USA 98(11):6390-6395). In addition to the pro-angiogenic function, leptin may enhance endothelial cell growth (Bouloumie et al., 1998, Circ. Res. 83(10):1059-1066; Sierra-Honigmann et al., 1998, Science 281(5383):1683-1686) and suppress apoptosis through a Bcl-2-dependent mechanism (Artwohl et al., 2002, Int. J. Obes. Relat. Metab. Disord. 26(4):577-580). The role of leptin in neovascularization is supported additionally by the observation that the hormone can increase the levels and activity of enzymes involved in angiogenesis, for example, matrix metalloproteinases (MMPs) 2 and 9 (Park et al., 2001, Exp. Mol. Med. 33(2):95-102; Kume et al., 2002, J. Histochem. Cytochem. 50(2):159-169). In addition to its involvement in endothelial cell function, leptin has been shown to act as a mitogen, transforming factor or migration factor for many different cell types, including smooth muscle cells (Oda et al., 2001, Kobe J. Med. Sci. 47(3):141-150), normal and neoplastic colon cells (Hardwick et al., 2001, Gastroenterology 121(1):79-90; Liu et al., 2001, Int. J. Oncol. 19(5):1009-1014), and normal and malignant mammary epithelial cells (Dieudonne et al., 2002, Biochem. Biophys. Res. Commun. 293(1):622-628; Laud et al., 2002, Mol. Cell. Endocrinol. 188(1-2):219-226).
Leptin can act as a mitogen and an angiogenic factor, suggesting that leptin may play a key role in cancer development and progression. In that context, leptin antagonists, acting as inhibitors of the activity associated with the leptin receptors, could find use in treatment of various kinds of cancer (Garofalo & Surmacz, 2006, J. Cell. Phys. 207:12-22, incorporated herein by reference in its entirety), such as glioma, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, ovarian cancer, endometric cancer and lung cancer. Recent research efforts focused on peptides related to the site III of leptin (Otvos et al., 2008, Biochim. Biophys. Acta 1783:1745-1754). These peptides were not true ObR antagonists, but rather partial agonists/antagonists depending upon the presence or absence of other ObR ligands. A therapeutically useful leptin antagonist should maintain the antagonistic activity in the presence of leptin or other ObR ligands, based on the fact that obese individuals have higher than normal levels of circulating leptin in their bodies (Frederich et al., 1995, J. Clin. Invest. 96(3):1658-1663; Ahima et al., 1996, Nature 382(6588):250-252; Boden et al., 1996, J. Clin. Endocrinol. Metab. 81(9):3419-3423; Sinha et al., 1996, J. Clin. Invest. 97(5):1344-1347; der Merwe et al., 1999, Int. J. Obes. Relat. Metab. Disord. 23(9):909-917; Thomas et al., 2000, Metabolism 49(10):1278-1284).
In the context of osteoporosis, fat metabolism is related to both arteriosclerosis and bone metabolism. Obese patients have higher risk of coronary artery disease and lower risk of osteoporosis. Recent studies by Ricci et al. (Am. J. Clin. Nutr. 2001, 73(2):347-352) showed that even moderate weight loss due to dieting in obese women leads to bone loss. A study from Denmark by Jensen et al. (J. Bone Miner. Res. 2001, 16(1):141-147) found a 4.2% decrease in whole body bone mineral and 4.0% decrease in the hip in women after 6 months of a diet that resulted in 5.5% weight loss (average 94 of 89 kg, or 207 to 196 lbs). The loss in bone density was attenuated by calcium supplementation. On the other hand, a study of 130 young women with anorexia showed a high prevalence of fractures and of low bone density. The bone density was related to weight at all skeletal sites.
Leptin appears to have a profound effect on bone density. Some authors, such as Mundy (Ann. Intern. Med. 2000, 133(10):828-830), proposed that leptin regulation was responsible for increased body weight as well as increased bone density. Mice who have congenital absence of leptin (ob/ob) are obese and have very high bone density. Leptin makes them lose both fat and bone. Leptin injected into the brain of animals will inhibit bone formation at doses lower than those that cause loss of body weight. Based on this evidence, an antagonist of the leptin receptor would be expected to promote bone formation in an affected individual.
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints. Rheumatoid arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue under the skin. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in its chronicity and progression. About 1% of the world's population is afflicted by rheumatoid arthritis. Rheumatoid arthritis affects women three times more often than men, and it can first develop at any age. The risk of first developing the disease (the disease incidence) appears to be greatest for women between 40 and 50 years of age, and for men somewhat later. It is a disabling and painful condition, which can lead to substantial loss of functioning and mobility.
Various treatments are available. Non-pharmacological treatment includes physical therapy, orthoses and occupational therapy. Analgesia (painkillers) and anti-inflammatory drugs, including steroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs) are often required to inhibit or halt the underlying immune process and prevent long-term damage. In recent times, the newer group of biologics has increased treatment options.
While rheumatoid arthritis primarily affects joints, problems involving other organs of the body are known to occur. Extra-articular (“outside the joints”) manifestations other than anemia (which is very common) are clinically evident in about 15-25% of individuals with rheumatoid arthritis. It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it—for example, lung fibrosis from methotrexate or osteoporosis from corticosteroids.
The arthritis of joints known as synovitis is inflammation of the synovial membrane that lines joints and tendon sheaths. Joints become swollen, tender and warm, and stiffness limits their movement. With time RA nearly always affects multiple joints, most commonly small joints of the hands, feet and cervical spine, but larger joints like the shoulder and knee can also be involved. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.
Rheumatoid arthritis is a form of autoimmunity, the causes of which are still incompletely known. It is a systemic (whole body) disorder principally affecting synovial tissues. There is no known cure for rheumatoid arthritis, but many different types of treatment can alleviate symptoms and/or modify the disease process. Most authorities believe that most RA should be treated by at least one specific anti-rheumatic medication, also named DMARD, to which other medications and non-medical interventions can be added as needed. Cortisone injections can be valuable adjuncts to a long-term treatment plan, and using low dosages of daily cortisone (e.g., prednisone or prednisolone, 5-7.5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment.
Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics. Examples of chemically synthesised DMARDs are: azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline and sulfasalazine (SSZ). An example of a cytotoxic drug is cyclophosphamide. Examples of biological agents (biologics) are: tumor necrosis factor alpha (TNFα) blockers (such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi)), Interleukin 1 (IL-1) blockers (such as anakinra (Kineret)), monoclonal antibodies against B cells (such as rituximab (Rituxan)), T cell costimulation blocker (such as abatacept (Orencia)) and Interleukin 6 (IL-6) blockers (such as tocilizumab (an anti-IL-6 receptor antibody) (RoActemra, Actemra)). Examples of anti-inflammatory agents include glucocorticoids and non-steroidal anti-inflammatory drug (NSAIDs, most also act as analgesics). Examples of analgesics include paracetamol (acetaminophen in US and Canada), opiates, diproqualone and lidocaine topical.
Obesity may aggravate RA (Gomez et al., 2009, J. Mol. Endocrinol. 43:11-18). Although increased joint loading has been proposed to explain these functional links, the positive association between obesity and rheumatoid disease was identified not only in weight-bearing joints, but also in the hand, suggesting an involvement of an obesity-related metabolic factor (Magliano, 2008, Menopause Int. 14:149-154). Leptin might contribute to pathogenesis of RA, as suggested by the observations that leptin levels are higher in individuals with RA then in healthy people and leptin can increase IL-8 production by synovial fibroblasts from RA patients (Gomez et al., 2009, J. Mol. Endocrinol. 43:11-18). However, the molecular mechanism linking leptin to RA is still unclear (Otero et al., 2006, Arthritis Rheum. 48:404-409).
Osteoarthritis (OA, also known as degenerative arthritis or degenerative joint disease) is a group of diseases and mechanical abnormalities involving degradation of joints, including articular cartilage and the subchondral bone next to it. Clinical manifestations of OA may include joint pain, tenderness, stiffness, creaking, locking of joints, and sometimes local inflammation. In OA, a variety of potential forces (hereditary, developmental, metabolic, and mechanical) may initiate processes leading to loss of cartilage (a strong protein matrix that lubricates and cushions the joints). As the body struggles to contain ongoing damage, immune and regrowth processes can accelerate damage (Brandt et al., 2008, Med. Clin. N. Am. 93(1):1-24). When bone surfaces become less well protected by cartilage, subchondral bone may be exposed and damaged, with regrowth leading to a proliferation of ivory-like, dense, reactive bone in central areas of cartilage loss, a process called eburnation. The patient increasingly experiences pain upon weight bearing, including walking and standing. As a result of decreased movement because of the pain, regional muscles may atrophy, and ligaments may become more lax.
OA is the most common form of arthritis and the leading cause of chronic disability in the United States. OA affects nearly 27 million people in the United States, accounting for 25% of visits to primary care physicians, and half of all NSAID (Non-Steroidal Anti-Inflammatory Drugs) prescriptions. It is estimated that 80% of the population will have radiographic evidence of OA by age 65, although only 60% of those will show symptoms. In the United States, hospitalizations for osteoarthritis soared from about 322,000 in 1993 to 735,000 in 2006.
Osteoarthritis is not to be confused with rheumatoid arthritis, an autoimmune disease with joint inflammation as a main feature. A common misconception is that OA is due solely to wear and tear, since OA typically is not present in younger people. However, while age is correlated with OA incidence, this correlation may illustrate that OA is a process that takes time to develop, or that repair and regeneration that may keep pace with damage in the joints of younger people do slow with age. There is sometimes a diagnosable underlying cause for OA, in which case it is described as secondary OA. In the majority of cases no cause can be identified, described as primary OA. “Degenerative arthritis” is often used as a synonym for OA, but the latter involves both degenerative and regenerative changes.
The main symptom of OA is acute pain, causing loss of ability and often stiffness. “Pain” is generally described as a sharp ache, or a burning sensation in the associate muscles and tendons. OA can cause a crackling noise (called “crepitus”) when the affected joint is moved or touched, and patients may experience muscle spasm and contractions in the tendons. Occasionally, the joints may also be filled with fluid. Humid and cold weather increases the pain in many patients. OA commonly affects the hands, feet, spine, and the large weight bearing joints, such as the hips and knees, although in theory, any joint in the body can be affected. As OA progresses, the affected joints appear larger, are stiff and painful, and usually feel worse, the more they are used throughout the day, thus distinguishing it from rheumatoid arthritis.
Treatment of OA consists of exercise, manual therapy, lifestyle modification, medication and other interventions to alleviate pain. Medication used to treat OA includes paracetamol (acetaminophen), non-steroidal anti-inflammatory drugs (such as diclofenac, ibuprofen, naproxen, ketoprofen, and COX-2 selective inhibitors, such as celecoxib, rofecoxib and valdecoxib), intra-articular corticosteroids, opioid analgesic (such as morphine or codeine), topical NSAIDs (diclofenac, ibuprofen, and ketoprofen), creams and lotions containing capsaicin, injections of hyaluronic acid or glucocorticoids (such as hydrocortisone).
Both metabolic and biochemical mechanisms contribute to the onset of OA (Pelletier et al., 2004, Bone 34:527-538). OA is strongly correlated with a high body mass index (Felson et al., 1988, Ann. Intern. Med. 109:18-24) and weight loss is associated with decreased disease progression (Christensen et al., 2007, Ann. Rheum. Dis. 66:433-439), suggesting a functional biochemical link between obesity and OA (Sandell, 2009, Arthritis Rheum. 60:2858-2860; Gomez et al., 2009, J. Mol. Endocrinol. 43:11-18). Indeed, recent data point out to leptin as the link between obesity and inflammatory osteoarthritic degeneration (Fantuzzi, 2005, J. Allergy Clin. Immunol. 115:911-919; Gomez et al., 2009, J. Mol. Endocrinol. 43:11-18; Lago et al., 2008, Nat. Clin. Pract. Rheumatol. 3:716-724; Otero et al., 2006, Drug News Perspect. 19:21-26; Vuolteenaho et al., 2009, Mediators Inflamm. 345838).
There is compelling evidence that leptin is implicated in the pathology of OA. Leptin-deficient mice are protected from OA, implying that leptin has a pro-degenerative function in cartilage (Griffin et al., 2009, Arthritis Rheum. 60:2935-2944). Indeed, leptin expression is increased in OA human cartilage compared to normal cartilage. In cultured cartilage explants, leptin can induce the expression of several pro-inflammatory mediators, i.e., iNOS, cyclooxygenase (COX) 2, nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL-6 and IL-8) through the activation of nuclear factor (NF)-κB, ERK1/2 and other pathways (Vuolteenaho et al., 2009, Mediators Inflamm. 345838). In cultured human and murine chondrocytes, type 2 NO synthase (NOS2) is synergistically activated by leptin and interferon-γ or IL-1 (Otero et al., 2003, Arthritis Rheum. 48:404-409; Otero et al., 2007, Life Sci. 81:1452-1460). In addition, leptin can induce the synthesis of matrix metalloproteinases (MMP) involved in cartilage damage, such as MMP-9 and MMP-13 (Gomez et al., 2009, J. Mol. Endocrinol. 43:11-18). It is hypothesized that increased OA incidents in females could be due to higher, relative to males, circulating leptin levels (Teichtahl et al., 2005, Med. Hypotheses 65:312-315).
Inflammatory bowel disease (IBD) is a term generally used to refer to conditions such as Crohn's disease (CD) and ulcerative colitis (UC), and, to a lesser extent, indeterminate colitis and infectious colitis. Inflammatory bowel diseases are chronic recurrent inflammatory diseases of unclear etiology (and thus classified as “idiopathic”), affecting the small intestine and colon. IBD may involve either or both the small and large bowel.
Pathologic findings are generally not specific, although they may suggest a particular form of IBD. “Active” IBD is characterized by acute inflammation. “Chronic” IBD is characterized by architectural changes of crypt distortion and scarring. The term “crypt” refers to a deep pit that protrudes down into the connective tissue surrounding the small intestine. Crypt abscesses (active IBD characterized by the presence of neutrophils in crypt lumens) can occur in many forms of IBD, not just UC. Under normal conditions the epithelium at the base of the crypt is the site of stem cell proliferation and the differentiated cells move upwards and are shed 3-5 days later at the tips of the villi. This normal process, necessary for proper bowel function, is interrupted by IBD.
UC involves the colon as a diffuse mucosal disease with distal predominance. The rectum is virtually always involved, and additional portions of colon may be involved extending proximally from the rectum in a continuous pattern. Most often UC occurs in young people 15 to 40 years of age. UC occurs only in the inner lining of the colon (large intestine) or rectum. When it is localized in the rectum, it is called “proctitis.”
CD is a chronic inflammatory disease that has periods of remission (time when person feels well) and relapse (when a person feels ill). CD is an inflammation and ulceration process that occurs in the deep layers of the intestinal wall. The most common areas affected are the lower part of the small intestine, called the ileum, and the first part of the colon. This type of CD is called ileocolitis. CD can infrequently affect any part of the upper gastrointestinal tract. Aphthous ulcers, which are similar to cold sores, are common. Ulcers can also occur in the esophagus, stomach and duodenum.
Therapy for IBD has historically included administration of corticosteroids. However drawbacks of long term corticosteroid therapy include masking (or induction) of intestinal perforation, osteonecrosis and metabolic bone disease. Additional problems relate to development of corticosteroid dependency (Habnauer, 1996, New England Journal of Medicine 334(13):841-848). Aminosalicylates such as sulfasalazine and mesalamine have been used to treat mild or moderately active UC and CD, and to maintain remission. Immunomodulatory drugs such as azathioprine and mercaptopurine have been used in long term treatment for patients with IBD. Common complications with both of these drugs include pancreatitis, which occurs with an incidence of 3-15% of patients, and bone marrow suppression, which requires regular monitoring. More potent immunosuppressive drugs such as cyclosporine and methotrexate have been employed, but toxicity of these drugs limits their use to specific situations of refractory disease states. Other therapeutic approaches include antibiotic therapy and nutritional therapy. Often, therapy involves a combination of the above-described drug therapies in addition to surgical resection of the bowel. There is no cure for IBD. Ultimately, the chronic and progressive nature of IBD demands a long-term treatment that maximizes the local anti-inflammatory effect while minimizing the global systemic effect on the immune system.
Chronic inflammatory disorders such as CD typically demonstrate periods of remission between intervals when the inflammatory is active and requires acute treatment. This is an example of a circumstance wherein it is known beforehand that an individual will develop, or is likely to develop an inflammatory disorder.
Irritable bowel syndrome (IBS) is a disorder of the bowel which is distinct from IBD. IBS affects at least 10% to 20% of adults in the U.S. IBS is the most common disorder diagnosed by gastroenterologists and one of the top ten most frequently diagnosed conditions among U.S. physicians. IBS is classified as a “functional gastrointestinal disorder,” wherein there is a disturbance in bowel function. IBS is not a considered a disease, but rather a syndrome, i.e., a group of symptoms. The symptoms typically include chronic abdominal pain/discomfort, and irregular bowel function, e.g., diarrhea, constipation, or alternating diarrhea and constipation. Unlike IBD, MS does not cause inflammation. IBS sufferers show no sign of disease or abnormalities on examination of the colon. Thus, though IBD and IBS share some similar symptoms, particularly cramping and diarrhea, the underlying disease process is quite different. MD involves inflammation or destruction of the bowel wall, which can lead to deep ulcerations and narrowing of the intestines. IBS is a disorder of the gastrointestinal (GI) tract for which no apparent cause can be found. An individual can simultaneously have both IBS and an inflammatory disorder such as IBD. When this occurs, imprecise diagnosis may lead to inadequate medical intervention.
Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition, and development of mesenteric white adipose tissue (WAT) hypertrophy. Increasing evidence suggests that adipokines synthesized either in WAT or in immune cells are involved in these manifestations of IBD (Karmiris et al., 2006, Inflamm Bowel Dis. 12(2):100-5). Among adipokines, leptin holds a fundamental role. Preliminary studies have shown over-expression of leptin in mesenteric WAT of patients with Crohn's disease (CD) and significant alterations of circulating serum levels of this adipokine in IBD. In animal models of intestinal inflammation, existing data suggest that leptin is a pivotal mediator of inflammation. Interesting therapeutic interventions based on these data have been suggested. A specific role for hypertrophic WAT has also been implicated in CD. Further efforts with experimental and clinical studies are needed to better understand the role of leptin in IBD.
There is thus still great need for a leptin-based antagonist that acts as such in the presence or absence of other leptin receptor ligands. The present invention addresses and meets these needs.